1. Field Of The Invention
The primary aspect of this invention is a process for forming 3-enol-ethers from 3-oxo-.DELTA..sup.4 -11-hydroxy steroidal compounds by reacting the 3-oxo-.DELTA..sup.4 -11-hydroxy steroid with triethyl orthoacetate in the presence of a substantial amount of ethanol. This aspect contributes to a novel process for preparing 6-halo-.DELTA..sup.4,6 - and .DELTA..sup.1,4,6 -pregnatrienes, particularly the 6-chloro-.DELTA..sup.1,4,6 -pregnatriene-11,17.alpha.,21-triol-3,20-diones and the corresponding 21-acetates.
2. Prior Art
In the preparation of active steroidal compounds for use as, for example anti-inflammatory drugs, it is often necessary to start with a readily obtainable compound, then performing a substantial number of steps which steps might include reacting one moiety of the compound to form a protecting group then reacting another moiety of the compound as desired. Through this procedure an extensive series of steps may be required to obtain the desired product and at each step there are certain yield losses which carried over the various steps may amount to a substantial and expensive yield loss over the entire process. Thus, in the field of steroid chemistry, researchers constantly work to develop more effective reaction schemes to increase overall yields by decreasing the number of steps required in a reaction sequence, by increasing yield for any particular step, or both. The overall yield may be improved either by providing a process wherein substantially all the starting material is reacted to form the desired product or side reactions are minimized.
An important step in many reaction sequences to form a 6-halo-.DELTA..sup.4,6 - or .DELTA..sup.1,4,6 -pregnatriene involves the conversion of a "cortisol-like" compound having a 3-oxo-.DELTA..sup.4 group to an enolether (i.e. formation of a 3-alkoxy-.DELTA..sup.3,5 intermediate) by reacting the 3-keto-.DELTA..sup.4 -steroid with a lower alkyl orthoformate in a suitable solvent such as dioxane in the presence of an acid catalyst such as p-toluenesulfonic acid. However, in starting from a readily available compound such as cortisol (hydrocortisone; 11.beta., 17.alpha., 21-trihydroxy-3,20-dioxopregn-4-ene) which has a reactive hydroxy at 21 and 11.beta., it has previously been shown that it is preferable to first react the cortisol (indicated as I, below) with formaldehyde and methylene chloride in hydrochloric acid to form a bis-methylenedioxy-(BMD) compound indicated as II below, i.e. ##SPC1##
See for example U.S. Pat. Nos. 2,888,456 and 288,457, both to Beryler and Sarett of Merck.
To then prevent the formation of a .DELTA..sup.11(9) derivative during the subsequent reaction with the lower alkyl orthoformate in acid through dehydration of the OH at 11.beta. and the H at 9, the 11.beta.-OH is first oxidized with e.g. chromic acid in sulfuric acid in dimethylformamide (DMF), i.e. ##SPC2##
Compound III is then treated with the lower alkyl orthoformate and acid to form the desired enol-ether (IV) which then may be treated further as required, i.e. ##SPC3##
where R = lower alkyl
It has been suggested in U.S. Pat. No. 3,082,224 to Weinstock that the dehydration problem can be solved by reacting a cortisol or cortisol 21-ether with a lower alkyl orthoformate in a solvent consisting solely of the corresponding lower alkanol and an acid catalyst. Employing this method, dehydration may allegedly be reduced to less than 10% and the 3-enol ether may be obtained in yields of 65% to 90%.
Another patent which discusses the formation of the intermediate 3-enol ether of the type mentioned above is U.S. Pat. No. 3,087,927. In that reaction sequence, the starting material was, e.g., 16-hydroxy cortisol or 16-hydroxy-cortisone. The patent discloses that these materials may be reacted in the presence of a mineral acid with an orthoester of the formula EQU R.sup.3 C (OR.sup.4).sub.3
wherein R.sup.3 is H or lower alkyl (C 1-3) and R.sup.4 is lower alkyl such as methyl and ethyl, to give a reaction product such as ##SPC4## Specifically, the examples show the reaction is carried out in dioxane with a small amount of methanol and sulfuric acid with trimethyl orthoformate. No mention is made in the disclosure of the patent of the dehydration problem discussed in U.S. Pat. No. 3,082,224.
Thus the prior art suggests that 11-hydroxy-.DELTA..sup.4 -pregnene-3-ones could be reacted to form the corresponding enol ether by using:
1. trialkyl orthoformate using a major amount of a solvent such as dioxane and a minor amount of the corresponding lower alkanol (i.e. trimethyl orthoformate with methanol or triethyl orthoformate with ethanol),
2. using triethyl orthoacetate with a major amount of a solvent such as dioxane with a minor amount of ethanol or,
3. using triethyl orthoformate with ethanol as the sole solvent.
In each of these cases an acid catalyst is used to allow the reaction to go at the desired rate. It has been found that in the first case the major product is the .DELTA..sup.9(11) dehydration product, in the second case the reactants do not react, and in the third case there is some dehydration which takes place between the 11 and 9 position and the reaction does not go to completion. Thus in each reaction known in the art the yields of the desired enol ether are low and in an extensive sequence of steps, this yield of course, will be carried through and will cut down on the overall production of the desired end product.
It has now been found that by using the process of this invention to form a 3-enol-ether from a 3-oxo-.DELTA..sup.4 -11.beta.-hydroxy steroid the following advantages are realized:
1. Dehydration at the 9(11) position is substantially completely eliminated;
2. Because of (1) there is no need to first oxidize the 11-hydroxy to an oxo group for purposes of protection;
3. Yield of the enol-ether is increased (due in part to 1 and 2, above, and also due in part to the tendency of the reaction of the process of this invention to go to completion);
4. Inexpensive oxygenated hydrocarbon cosolvents such as glymes may be used with ethanol;
5. In reacting steroids having 17.alpha.,21-hydroxy moieties it is not necessary to protect these moieties via BMD or other methods; and
6. The above 5, advantages all contribute to a simpler process than previously known in the art.
Other advantages of the process of this invention will be apparent to those skilled in the art from reading the disclosure below.